Measuring the concentration of substances, particularly in the presence of other, confounding substances, is important in many fields, and especially in medical diagnosis. For example, the measurement of glucose in body fluids, such as blood, is crucial to the effective treatment of diabetes.
Diabetic therapy typically involves two types of insulin treatment: basal and bolus. Basal insulin refers to continuous, e.g. time-released insulin. Bolus insulin treatment provides additional doses of faster acting insulin to regulate fluctuations in blood glucose caused by a variety of factors, including the meal-time metabolization of sugars and carbohydrates, etc. Proper regulation of blood glucose fluctuations requires accurate measurement of the concentration of glucose in the blood. Failure to do so can produce extreme complications, including blindness or impaired circulation in the extremities, which can ultimately deprive the diabetic of use of his or her fingers, hands, feet, etc.
Multiple methods are known for measuring the concentration of analytes in a blood sample, such as, for example, glucose. Such methods typically fall into one of two categories: optical methods and electrochemical methods. Optical methods generally involve reflectance or absorbance spectroscopy to observe the spectrum shift in a reagent. Such shifts are caused by a chemical reaction that produces a color change indicative of the concentration of the analyte. Electrochemical methods generally involve, alternatively, amperometric or coulometric responses indicative of the concentration of the analyte. See, for example, U.S. Pat. Nos. 4,233,029 to Columbus, 4,225,410 to Pace, 4,323,536 to Columbus, 4,008,448 to Muggli, 4,654,197 to Lilja et al., 5,108,564 to Szuminsky et al., 5,120,420 to Nankai et al., 5,128,015 to Szuminsky et al., 5,243,516 to White, 5,437,999 to Diebold et al., 5,288,636 to Pollmann et al., 5,628,890 to Carter et al., 5,682,884 to Hill et al., 5,727,548 to Hill et al., 5,997,817 to Crismore et al., 6,004,441 to Fujiwara et al., 4,919,770 to Priedel, et al., 6,054,039 to Shieh, and 6,645,368 to Beaty et al., which are hereby incorporated by reference in their entireties.
For the convenience of the user, reducing the time required to display an indication of the glucose level in a blood sample has been a goal of system designers for many years. Test times have been reduced from early colorimetric products that took approximately two minutes to display a reading, to test times on the order of 20-40 seconds. More recently, test times shorter than ten seconds have been described (see, for example, U.S. Pat. Nos. 7,276,146 and 7,276,147), and several products currently on the market advertise test times of about five seconds. Shorter test times of less than two seconds have been discussed in various patent applications (see, for example, U.S. Patent Application Publication Nos. 2003/0116447A1 and 2004/0031682A1). But the true utility of a short test time is not completely reached with these teachings in terms of the results being substantially unaffected by confounding interferents.
An important limitation of electrochemical methods for measuring the concentration of a chemical in blood is the effect of confounding variables on the diffusion of analyte and the various active ingredients of the reagent. Examples of limitations to the accuracy of blood glucose measurements include variations in blood composition or state (other than the aspect being measured). For example, variations in hematocrit (concentration of red blood cells), or in the concentration of other chemicals in the blood, can effect the signal generation of a blood sample. Variations in the temperature of the blood samples is yet another example of a confounding variable in measuring blood chemistry. The utility of a reported blood glucose response after a short test time is questionable in applications where the results are not compensated for other sample variables or interferents such as hematocrit and temperature.
With respect to hematocrit in blood samples, prior art methods have relied upon the separation of the red blood cells from the plasma in the sample, by means of glass fiber filters or with reagent films that contain pore-formers that allow only plasma to enter the films, for example. Separation of red blood cells with a glass fiber filter increases the size of the blood sample required for the measurement, which is contrary to test meter customer expectations. Porous films are only partially effective in reducing the hematocrit effect, and must be used in combination with increased delay time and/or AC measurements (see below) to achieve the desired accuracy.
Prior art methods have also attempted to reduce or eliminate hematocrit interference by using DC measurements that include longer incubation time of the sample upon the test strip reagent, thereby reducing the magnitude of the effect of sample hematocrit on the measured glucose values. Such methods also suffer from greatly increased test times.
Other attempts to reduce or eliminate hematocrit and temperature interference are taught in U.S. Pat. No. 7,407,811, as well as in the disclosures of the parent cases to this application, in which an AC potential of a low amplitude is applied to a sample in order to determine certain sample characteristics based on phase angle (also referred to herein as “phase”) and admittance information from the current response to the AC excitation signal. As it is taught, multiple frequencies of an AC excitation signal are applied in sequential blocks, followed by a conventional DC excitation signal. However, those disclosures indicate the inventors' belief that there are limits to the minimum time each frequency must be applied in order to obtain useful, consistent and reasonably reproducible information, from both the AC and DC excitation signals. Even then, the shortest total test time practically achievable from a complete AC method was 3 seconds. Alternatively, to achieve a practical analysis in less than 3 seconds, a limit was placed on the number of frequency blocks used during the AC excitation, i.e. 2 blocks rather than 4. However, reducing the number of frequency blocks used may have a negative affect on the level of accuracy attainable in correcting for multiple interferents, e.g., hematocrit and temperature. As has been taught in these previous disclosures of AC excitation, correction of the indicated glucose can be achieved for multiple interferents by obtaining multiple correction factors, such as the phase and/or admittance response data resulting from multiple frequencies of an AC signal excitation. Multiple correction factors are particularly beneficial when they measure individual or different aspects of interferents or when they are influenced by one interferent more than the other.
Furthermore, the correction factors or even the measurements used for determining the desired analyte concentration may also be used for calculating and optionally reporting additional parameters such as the hematocrit level or hematocrit range of the blood. By reducing the number of potential correction factors, e.g. measuring the phase and/or admittance from only two rather than three, four or more frequencies of an AC excitation, potentially useful information could be forsaken. Information such as hematocrit level or hematocrit range, for example, could be useful information for a user, especially for health care providers in a clinical setting where patients who are more susceptible to medically significant abnormal hematocrits due to illness or treatment could be identified during a routine blood glucose test. Providing a hematocrit level, for example, in addition to the glucose concentration would be a valuable piece of information in some settings, which could be lost as a result of the solutions presented by the prior art.
Thus, a system and method are needed that more accurately measure blood glucose, even in the presence of confounding variables, including variations in hematocrit, temperature and the concentrations of other chemicals in the blood. Further needed are such system and method with test times of less than 2 seconds. A system and method are likewise needed that accurately measure any medically significant component of any biological fluid with test times of less than 2 seconds. It is an object of the present invention to provide such a system and method.